Tachykinins belong to a family of short peptides that are widely distributed in the mammalian central and peripheral nervous system (Bertrand and Geppetti, Trends Pharmacol. Sci. 17: 255-259 (1996)). They share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH2. The three major tachykinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) with preferential affinity for respectively three distinct receptor subtypes, termed Neurokinin (NK)-1, NK-2, and NK-3.
Compounds showing selective affinity simultaneously to both NK-1 and NK-3 receptors are named dual NK-1/NK-3 receptor antagonists. For example, 2-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide (Compound A), having the following structure:
has been found to be effective as a dual NK-1/NK-3 receptor antagonist.
Compound A is also known in an anhydrous crystalline form. Thus Compound A in an anhydrous crystalline form is described in WO2011023733, e.g., having 2 theta angles occurring at 4.3±0.1, 7.9±0.1, 9.8±0.1, 10.7±0.1, 10.8±0.1, 13.3±0.1, 14.0±0.1, 15.1±0.1 degrees, which correspond respectively to d-spacing at 20.4, 11.1, 9.0, 8.3, 8.2, 6.6, 6.3 and 5.9 Angstroms (Å) (hereinafter “Form 1”).
Compound A or pharmaceutically acceptable salts thereof, including its crystalline Form 1, are known, inter alia to be useful in the treatment of sex hormone diseases, including hot flushes (WO 2016/184829).
It is essential that, when being administered to a subject in need thereof, Compound A reaches the site of action at an amount and for a duration, as defined by the pharmacokinetic (PK) exposure, that is sufficient for a therapeutic effect to occur, while the exposure level of Compound A is not too high that it might result in treatment induced adverse reactions. Therefore there are two key parameters relating to the PK of Compound A to ensure that a dose of this drug administered to a patient consistently reaches levels of exposure so that it produces the desired therapeutic effect while minimising the potential for adverse effects. First is the PK variability which is a measure of the variation in exposures achieved with the same dose of a drug. The PK variability which is typically measured as the Coefficient of Variation as a percent (CV %) should be low such that when any given dose of a drug is administered the plasma levels (both maximum plasma concentration that a drug achieves [Cmax] and exposure [Area under the Curve [AUC]] in subjects are similar. Certainly the CV % achieved for these measures with any given dose of a particular drug should be typically <50%. Second is the bioavailability of Compound A, which defines the proportion of a drug from an administered dosage form that reaches the systemic circulation and therefore dictates the level of drug exposure. The bioavailability achieved with a dose of a particular drug when administered to a subject needs to be able to reach the desired therapeutics levels of exposure.
It is known that the formulation of a drug (dosage form) namely the process by which the active drug is combined with other different inactive chemical substances (excipients), to produce a final drug product can influence these two critical PK parameters. However such formulations also need to maintain the stability of the active drug ideally at ambient conditions for long term storage. Maintenance of stability of the active drug is therefore the third key parameter required for development of a novel drug product formulation.
Previously, Compound A as Form 1, was formulated for oral administration as solid dosage forms of drug product and these were administered to human subjects in both Phase 1 and 1b/2 clinical studies.
The PK data from a tablet solid dose formulation administered as single oral doses of either 100 mg or 200 mg of Compound A (Form 1) to 16 healthy male and female volunteers in a Phase 1 study is summarized in Table 1. The results revealed an unacceptable level of PK variability as measured by CV % that ranged from 69.9% to 120%, and high Ratios of Minimum & Maximum PK parameters ranging from 9.8 to 20.1.
TABLE 1PK data from a single dose Phase 1 clinical study with CompoundA(Form1) using a solid dose tablet drug productDevelopment Form: Anhydrous crystalline form (Form1)Study populations: Male and Female Healthy VolunteersPKDoseGeometricMinimumMaximumRatioFormulationparameter(mg)NMeanCV %(Min)(Max)(Max:Min)SolidCmax10016880101120241120.1tablet{circumflex over ( )}(ng/mL)200795120169226813.4dosesAUC0-24100330969.967966259.8(single dose)(ng · hr/mL)200442476.312371293710.5Key:CV % = Coefficient of variation percent{circumflex over ( )}Powder blend of Compound A anhydrous crystalline form (Form1) which has been compressed to obtain a tablet drug product
A second Phase 1b/2 clinical study was undertaken involving repeated dosing of an additional solid dose hard gelatin capsule formulation of Compound A (Form 1) in post-menopausal women experiencing moderate to severe vasomotor symptoms. The doses investigated were 50, 100, 150 and 300 mg, orally administered once daily for 14 days. There were 13 or 15 subjects per dose group. All doses were given using the 50 mg capsule formulation. To achieve unit doses higher than 50 mg, appropriate multiples of capsules were concomitantly administered to patients in each of the dose groups. Steady-state PK results after 14 days dosing are presented in Table 2. Once more an unacceptably high level of PK variability was observed in this repeat dose study with the hard capsule solid dosage drug product as measured by CV % that ranged from 64.7% to 131.2%, and high Ratios of Minimum & Maximum PK parameters ranging from 6.1 to 36.5.
TABLE 2Steady-state PK data from a repeat dose Phase 1b/2 clinical study with CompoundA (Form1) using a solid dose hard gelatin drug productDevelopment Form: Anhydrous crystalline form (Form1)Study populations: Post-menopausal females experiencing moderate to severe vasomotor symptomsPKDoseGeometricMinimumMaximumRatioFormulationparameter(mg)NMeanCV %(Min)(Max)(Max:Min)Solid hardCmax501552287.9142154410.9gelatin(ng/mL)10014841107.2181385621.3capsule150151188131.2208590328.4doses300132852116.5237865336.5(Steady-stateAUC0-245015234264.791555406.1Day 14)(ng · hr/mL)10014354286.37781093814.115015516488.715641616310.3300131482399.724577968532.4Key:CV % = Coefficient of variation percent{circumflex over ( )}Powder blend of Compound A anhydrous crystalline form (Form1) which has been encapsulated in a hard gelatin capsule. The specific composition of a solid dosage hard gelatin capsule formulation containing 50 mg of Compound A is provided in Table 3.
The efficacy assessments demonstrated that ‘maximum efficacy’ in this Phase 1b/2 study was achieved with a once daily dose hard gelatin drug product of 150 mg Compound A (requiring three 50 mg hard gelatin capsules). Repeat once-a-day dosing of 150 mg Compound A gave a geometric mean exposure AUC0-24 5164 ng·hr/mL of the drug at Day 14.
TABLE 3Composition of solid dose hard gelatin capsule formulationcontaining 50 mg of Compound A[Form 1] administeredin the Phase 1b/2 study.Quantity per CapsuleIngredients(mg)FunctionalityCompound A (Form1)50.00ActiveIntra-granular IngredientsLactose Monohydrate (Spray47.10Filler AgentDried)Microcrystalline Cellulose,33.04Filler Agent(Avicel PH-101)Hypromellose 29105.55BinderCroscarmellose Sodium1.67DisintegrantPurified Water (removed during22.22Granulatingprocessing)SolutionExtra-granular ingredientsLactose Anhydrous (Super Tab21.89Filler Agent21AN)Microcrystalline Cellulose (PH-35.00Filler Agent102)Croscarmellose Sodium5.25DisintegrantMagnesium Stearate1.75LubricatingAgentTotal [intra- and extra-granular]201.25Empty Hard Gelatin Capsule,1 unitCapsule ShellSize 2, Opaque White/White
Despite levels of drug exposure being achieved that were efficacious in the Phase 1b/2 clinical study, neither of these solid dose formulations of Compound A are suitable for further clinical development due to the very high PK variability observed in these human subjects.
Therefore, there is a need for a novel pharmaceutical formulation of Compound A or a pharmaceutically acceptable salt thereof that provides a reduced human subject PK variability, thereby reducing the likelihood of very high drug exposures being reached in individual patients and ensuring a much safer medicine; as well as avoiding too low exposures which would mean patients do not receive a therapeutically beneficial dose of Compound A. Such formulations must also have sufficient bioavailability to be able to achieve therapeutic levels of plasma exposure of Compound A. In addition such formulations must provide good stability of Compound A during manufacture and subsequent distribution and long term storage of the drug product.
A soft gelatin capsule formulation could provide an approach to address these needs. However, it is known to those in the art, that formulating drugs into solution for encapsulation into a soft gelatin capsule can be challenging and can present many problems (Gullapalli, 2010). These challenges include the migration of the soft gelatin constituents between the formulation, the shell and external environments; nor must there be physical and chemical incompatibilities between the components. In addition, it can be difficult to identify liquid matrices in which an active ingredient is sufficiently soluble to dissolve the desired target dose in a suitably small volume to be encapsulated for oral administration; that does not precipitate out during the manufacturing process, upon storage for the duration of the required shelf-life, upon contract with the aqueous environment (dissolution) nor once administered in vivo. Also, it can be problematic to identify formulations in which drug substances are stable for long term storage encapsulated in the soft gelatin capsules as they are susceptible to both hydrolytic and oxidative instability.
These technical challenges have been unexpectedly overcome and the formulations according to the present invention address all the three key parameters described above.
Particularly, the present disclosure is based on, inter alia, our unexpected discovery of novel formulations of Compound A that provide remarkably reduced PK variability of Compound A and that can achieve therapeutic levels of plasma exposure. Furthermore, it was discovered that such formulations effectively solubilize Compound A in a volume suitable for oral administration and exhibit long-term storage stability at ambient conditions without recrystallization, precipitation, or phase separation.